Additional Alkylation Reactions

Introduction

The success of the aldol condensation and the Claisen condensation depends upon the fact that the value of the equilibrium constant for deprotonation of a carbon atom adjacent to a carbonyl group is such that significant concentrations of nucleophilic and electrophilic carbons are present in the reaction mixture simultaneously:

The reaction conditions required to effect an aldol or a Claisen condensation place a limit on our ability to effect direct alkylation of simple aldehydes, ketones, and esters. For example, suppose you wanted to prepare 2-butanone by methylation of acetone as shown in Equation 1.

While this reaction might look feasible on paper, the desired outcome is precluded by competition from both the aldol condensation and the Sn2 reaction shown in Equation 2.

In other words, nucleophilic aliphatic substitution competes with deprotonation; direct attack of the hydroxide ion on the methyl carbon of methyl bromide is preferred to attack at one of the methyl hydrogens of acetone. With other alkyl halides other pathways are possible. For example, with ethyl bromide both Sn2 and E2 reactions are viable alternatives, as indicated in Equation 3:

Complications such as those shown in Equations 2 and 3 have led chemists to develop other approaches to alkylation of aldehydes, ketones, and esters. This topic examines two of those alternatives.

Direct Alkylation

Perhaps the simplest way to effect direct alkylation of a simple aldehyde, ketone, or ester is to eliminate the possibility of aldol or Claisen condsations by converting essentially all the the starting material to its conjugate base. To do this requires a base that is stronger than hydroxide or alkoxide ion. One base that works well is lithium diisopropyl amide, LDA, the conjugate base of diisopropyl amine. This material is easily prepared by either of the two methods outlined in Scheme 1.

Scheme 1

Preparation of LDA

Treatment of diisopropyamine with n-butyl lithium involves an acid-base reaction that has an equilibrium constant of approximately 10¹². A solution of n-BuLi in THF is added to a solution of diisopropyl amine in the same solvent under an inert atmosphere at -78^oC.

The lower reaction in Scheme 1 involves addition of lithium metal to an excess of diisopropyl amine. This reaction is also generally performed at low temperatures under an inert atmosphere. It is analogous to the preparation of alkoxide ions by treatment of an alcohol with sodium, potassium, or lithium metal. LDA is available commercially, both as a solid and in solutions of known concentration.

Regardless of its source, LDA is a sterically hindered, non-nucleophilic base that readily abstracts a hydrogen atom from the a-carbon of aldehydes, ketones, and esters. Equation 4 provides a representative, yet informative, example of alkylation of a siimple ketone.

The isomeric products result from attack of either the C-2 enolate or the C-6 enolate on the methyl iodide. The product distribution depends on the reaction conditions.

Exercise 1A Draw the structure of the C-2 enolate. Don't include the Li ion.1A

Exercise 1B Draw the structure of the C-6 enolate. Don't include the Li ion. 1B

Exercise 2 Which enolate ion is more stable? the C-2 enolate the C-6 enolate

Exercise 3 Which product is kinetically favored? 2,2-dimethylcyclohexanone 2,6-dimethylcyclohexanone

4

In reaction 7, the pKa of the hydrogen atom alpha to the nitrile group is approximately 25, not as acidic as alpha protons in aldehydes, ketones, and esters, but acidic enough that the equilibrium constant for deprotonation of the starting material is about 10¹³.

5A

5B

5C

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Alkylation of 1,3-Dithianes

In our discussion of the nucleophilic addition of alcohols to aldehydes and ketones, we saw that the reaction of diols with aldehydes and ketones produces cyclic acetals and cyclic ketals. One example is shown in Equation 8.

It should not come as a surprise that treatment of an aldehyde with a dithiol generates a cyclic thioacetal. Scheme 2 illustrates this parallel in general terms.

Scheme 2

Generation of Cyclic Thioacetals

This reaction is of synthetic interest because of the change in acidity of the aldehydic hydrogen that occurs when the aldehyde is converted to the corresponding cyclic thioacetal. While the pKa of an aldehydic proton is approximately 45, it drops to approximately 32 in the cyclic thioacetal. Hence, deprotonation of the cyclic thioacetal with LDA is essentially complete; K_eq being approximately 10⁶. Scheme 3 presents a resonance-based interpretation of the greater acidity of cyclic thioacetals.

Scheme 3

Resonance to the Rescue

Because sulfur has empty 3d orbitals, the negative charge that initially resides on the carbon atom may be delocalized onto both adjacent sulfur atoms. This stabilizes the conjugate base, making deptotonation of the cyclic thioacetal feasible. A comparable acid-base reaction is not possible in cyclic acetals because the conjugate base is not stabilized by resonance; the oxygen atoms do not have d orbitals available to accomodate electron density.

However, the transformation suggested in Equation 9 may be accomplished indirectly by the 3-step sequence shown in Scheme 3.

Scheme 3

There's More Than One Way to Skin a Cat

The last step of this sequence, the work-up, involves hydrolysis of the thioacetal, a process that is facilitated by the Lewis acid mercuric chloride.

7A

7B

7C